1. Systems approach reveals photosensitivity and PER2 level as determinants of clock‐modulator efficacy
A911 pairs of gating and adaptation, with which the model accurately simulates the 3‐day LD dosing effect in NHPs (n = 8; mean ± SEM; Fig F) (left) and the magnitude of human PRC to a 6.7‐h light pulse (Khalsa et al, ), were found using the simulated annealing method (see Materials and Methods for details). The photosensitivity is normalized so that the maximum photosensitivity of initially estimated gatings becomes unified (center). 100% adaptation in photosensitivity means that Per1/2 gene transcription is no longer induced by light (right). B152 pairs of gating and adaptation with which simulated PRCs to a 12‐h light pulse are discontinuous were filtered out (left), which is caused by the slow adaptation exaggerating the light effect (right). C323 pairs of gating and adaptation were filtered out with which simulated light PRCs to a 6.7‐h light pulse have a too large phase shift between CT0 and CT6 (left) due to overestimated photosensitivity (center). Here, the human PRC to a 6.7‐h light pulse is adopted from (Khalsa et al, ). D327 pairs of gating and adaptation were filtered out with which the simulated PRCs to 3‐cycle 5‐h light pulses (left) have either a too large phase shift due to overestimated photosensitivity between CT6 and CT12 (center) or an abrupt jump between CT16 and CT20 due to an underestimated range of high photosensitivity zone (center). Here, the human PRC to 3‐cycle 5‐h light pulses is adopted from (Khalsa et al, ). E99 pairs of gating and adaptation with which the model fails to simulate the human PRC to a 6.7‐h light pulse (Khalsa et al, ) between CT15 and CT18 were filtered out (left). F10 pairs of gating and adaptation passed the filtering procedure. See Dataset EV2 for the values of the parameters describing the 10 pairs of gating and adaptation. G, HThe model with these 10 pairs of gating and adaptation (F) accurately simulates the human PRC to a 6.7‐h light pulse (left) and 3‐cycle 5‐h light pulses (right) (G). The model accurately predicts the human PRC to a 3‐h light pulse adopted from (Minors et al, ), which is not used in the estimation process (H).
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Mol Syst Biol, Volume: 15, Issue: 7, First published: 08 July 2019, DOI: ( /msb )